Peripheral neuropathy is the major complications of diabetes. There is a compelling need to develop effective therapeutic approaches specifically designed to improve neurological function in the damaged peripheral nervous system after diabetes. MicroRNA-146a (miR-146a) has been implicated in the regulation of multiple immune diseases. However, the role of miR-146a in diabetic peripheral neuropathy (DPN) has not been investigated. In a novel set of experiments, our preliminary data show that intravenous administration of miR-146a remarkably improved sciatic nerve vascular function, axonal myelination and peripheral nerve function in diabetic mice, indicating that miR-146a may have a beneficial effect on the clinical treatment of DPN. In this application, we therefore seek to investigate the mechanisms underlying the therapeutic effects of miR- 146a on DPN. We propose that miR-146a by improving vascular function and suppressing pro-inflammation factors ameliorates DPN. The associated hypotheses are: 1. Treatment with chemically engineered miR-146a improves neurological outcomes in DPN in dose and therapeutic window dependent manners. 2. Elevation of miR-146a levels suppresses its target genes, IRAK1/TRAF6 and their down-stream pro-inflammatory factors in vascular endothelial cells and monocytes of type II diabetic mice, thereby, leading to the improvement of neurovascular function and consequently ameliorating peripheral neuropathy. To investigate the effect of miR- 146a on neurological outcomes, type II diabetic mice which develop severe peripheral neuropathy will be treated with miR-146a at various time points and doses after onset of DPN. To investigate the underlying molecular mechanisms, the effects of miR-146a overexpression and knockdown on target genes and inflammatory genes that mediate miR-146a-enhanced neurovascular function will be determined. These studies are innovative and will provide novel insights into mechanisms underlying the neurological dysfunction of DPN and likely lead to the development of a new miRNA-based gene therapy.